The Government may own certain rights in the present invention pursuant to USPHS Grant Ca26475 and ACS grant IFN-3.
1. Field of the Invention
The present invention is directed to improved methods and compositions which incorporate interferon gamma for the treatment of viral infections and neoplastic disease. In particular, the present invention is directed to an improved interferon gamma preparation which exhibits a greatly enhanced activity over previously available preparation and, further, the use of interferon gamma preparations in treatment protocols designed to provide maximal antitumor and antiviral activity.
2. Description of the Related Art
Interferons (IFN-alpha, IFN-beta and IFN-gamma) are natural host proteins which have antiviral, immunoregulatory and antiproliferative activity. A number of clinical trials have examined interferons in order to assess their clinical potential. (For a review, see Borden (1983), "Interferons: In Pursuit of the Promise," in: 13th Int'l. Congress, Part E, Cancer Management, Mirand et al., eds., Alan R. Liss, N.Y., 287-296). Unfortunately, while certain interferons have demonstrated real promise for the control of certain types of cancer, for example, the use of IFN-alpha in hairy cell leukemia, they have for the most part been limited in their effectiveness and have not been found to be highly potent against most types of cancer tested. Further, interferon therapy has a number of important side efforts, in particular, bone marrow suppression. Therefore, a major challenge facing medical science is to increase the antitumor activity of the interferons while reducing or moderating their side effects.
One problem which has been identified with respect to IFN-gamma treatment is the apparent association of IFN-gamma preparations, including recombinantly-produced preparations, with an inhibitory activity. This IFN-gamma inhibitory activity was first identified and discussed by Fleischmann et al. (1979), Infec. and Immun., 26(3): 949-55, where it was observed that an inhibitor could be partially purified from IFN-gamma preparations, which inhibitor demonstrated a profound ability to block the antiviral activity of up to 400 units of interferon. Further studies by Lefkowitz et al. (Jrnl. Interferon. Res. (1985), Vol. 5: 85-99 and Vol. 5: 101-110) have demonstrated the existence of this inhibitory activity in a variety of interferon gamma preparations. Thus, an important step in maximizing the clinical usefulness of IFN-gamma would be to provide IFN-gamma preparations wherein this inhibitory activity has been minimized or removed altogether.
Further problems previously associated with IFN therapy has been the development of viral and tumor resistance to IFN-alpha and beta therapy that results in an apparent decreased sensitivity of these clinical targets to treatment. Attempts to alleviate this problem through increased dosages of IFN's have merely exacerbated the bone marrow toxicities associated in the IFN therapy. Accordingly, treatment regimens are needed which would provide both a decrease in the occurrence of IFN associated resistance and myelosppression while providing an enhanced IFN activity.